p38MAPK, Rho/ROCK and PKC pathways are involved in influenza-induced cytoskeletal rearrangement and hyperpermeability in PMVEC via phosphorylating ERM

Zhang, Chenyue; Wu, Ying; Xuan, Zinan; Zhang, Shujing; Wang, Xudan; Yu, Hao; Wu, Jun; Zhang, Shu

doi:10.1016/j.virusres.2014.07.027

Cited by 40 publications

(40 citation statements)

References 42 publications

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“…Despite these questionable results with rottlerin, it was recently demonstrated that PKC and other kinases such as Rho/Rock and p38MAPKK contribute to influenza-induced cytoskeletal changes and permeability increases in pulmonary microvascular endothelial cells via phosphorylating ezrin-radixin-moesin (ERM) family of membrane-cytoskeletal linker proteins. Therefore, it was suggested that inhibition of these phosphorylation pathways should block influenza virus replication [138]. These data confirm previous results where PKC inhibitors have been identified to reduce influenza virus replication [139].…”

Section: Additional Strategies That Interfere With Host Mechanismssupporting

confidence: 88%

Strategies for the Development of Influenza Drugs: Basis for New Efficient Combination Therapies

Steinmetzer¹,

Hardes²,

Böttcher‐Friebertshäuser³

et al. 2014

Topics in Medicinal Chemistry

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Only four drugs are approved for the specific treatment of acute influenza infections worldwide. These drugs address either the viral neuraminidase or the M2-channel but suffer from poor efficacy and the rapid emergence of drug resistances. Some additional drugs are launched in few countries, but their efficacy is relatively low and often limited to certain influenza strains. Ideally, new drugs should possess a broad potency against all influenza viruses and be less susceptible to the development of resistances. The propagation cycle of the influenza virus offers many possibilities for the development of new anti-influenza drugs. Various compounds addressing viral targets reached clinical development, from which the most-advanced candidate is the polymerase inhibitor favipiravir. A promising strategy could be also the inhibition of host targets and signaling pathways, e.g., by already approved kinase inhibitors, anti-inflammatory drugs, or immunomodulatory agents. However, the benefit of these agents has to be demonstrated in controlled clinical trials. A broader arsenal of approved drugs will offer the possibility for more efficient combinatorial therapies in the future. The first proof of concept studies for such multiple drug therapies in infected mice revealed beneficial effects. Moreover, this strategy should reduce the rapid emergence of resistant influenza strains.

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Section: Additional Strategies That Interfere With Host Mechanismssupporting

confidence: 88%

Strategies for the Development of Influenza Drugs: Basis for New Efficient Combination Therapies

Steinmetzer¹,

Hardes²,

Böttcher‐Friebertshäuser³

et al. 2014

Topics in Medicinal Chemistry

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“…Surprisingly, our data indicated a slight increase in virus release rate for the suspension cell line based on measured (HA) titer and flow cytometric data also indicated differences in the time course of viral infection. In agreement with previous reports demonstrating the influenza‐induced cytoskeletal rearrangement by phosphorylated ezrin , our data suggest a role of ezrin in early virus release for suspension cells as the intensity of ezrin protein spots were increased significantly at 8 and 32 hours post infection (hpi). Interestingly, various heterogeneous nuclear ribonucleoproteins (HNRNPs), which are known to bind actively influenza viral proteins and nucleic acid segments, were detected to be differentially expressed for suspension cells at 32 hpi.…”

Section: Introductionsupporting

confidence: 93%

“…For example, for ezrin, Bukong et al found that a knockdown inhibited virus trafficking towards the endoplasmic reticulum. A recent study of Zhang et al showed that three forms of kinases are involved in influenza‐induced cytoskeletal rearrangement via the phosphorylation of the ERM complex. This phosphorylation positively correlated with cell permeability of pulmonary microvascular endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

Ezrin and HNRNP expression correlate with increased virus release rate and early onset of virus‐induced apoptosis of MDCK suspension cells

Kluge

Genzel

Laus

et al. 2016

Biotechnology Journal

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With the aim to adapt high-yield adherent cell lines to suspension growth, Madin Darby canine kidney (MDCK) suspension cells were developed recently that achieved comparable influenza virus yields despite an early induction of apoptosis compared to the parental adherent cell line. For both cell lines, a comprehensive study under comparable infection conditions is performed comprising information on: time course of viral infection, antiviral state of cells, virus-induced apoptosis, and virus-induced cellular protein expression for early and late infection with influenza A/PuertoRico/8/34 H1N1. The proteomic analysis is performed with 2D differential gel electrophoreses followed by mass spectrometry. Based on flow cytometric data and on the differential expression of various stress and apoptosis-related proteins, the earlier onset of virus-induced apoptosis is confirmed for suspension cells. Surprisingly, the data indicated an increased virus release rate for suspension cells. These observations correlate with an increased expression of the apical marker protein ezrin, known to play a role in influenza-induced cytoskeletal rearrangement, and the differential expression of heterogeneous nuclear ribonucleoproteins, known to bind actively influenza viral proteins and play a central role in regulating gene expression. Based on these findings, additional studies towards the design of MDCK suspension cells with further increase in influenza virus yields will be performed.

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“…25 Previously, we showed that IV infection increased microvascular leakage in PMVECs, with the primary mechanism being related to activation of the Rho/ROCK, p38 MAPK, and PKC pathways, ultimately leading to ERM phosphorylation. 11 XDY is a classic traditional medicine that is used for treating viral pneumonia induced by IV infection. Previously, we showed that XDY administration reduced mortality rates in mice with viral pneumonia.…”

Section: Discussionmentioning

confidence: 99%

“…10 The results from in vitro studies demonstrated that XDY could protect the endothelial barrier by reversing permeability increases in PMVECs caused by IV infection. 11 However, the mechanisms by which XDY mitigates hyper-permeability in IV-infected PMVECs requires further investigation.…”

Section: Introductionmentioning

confidence: 99%

Xijiao Dihuang Decoction combined with Yinqiao Powder reverses influenza virus-induced F-actin reorganization in PMVECs by inhibiting ERM phosphorylation

Xuan

Zhang

et al. 2016

Journal of Traditional Chinese Medical Sciences

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Objective: It has been documented that ezrin/radixin/moesin (ERM) phosphorylation by the p38 mitogen-activated protein kinase (MAPK), Rho/ROCK, and protein kinase C (PKC) pathways leads to filamentous actin (F-actin) reorganization and microvascular endothelial cell hyperpermeability. In this study, we investigated the effects of Xijiao Dihuang Decoction combined with Yinqiao Powder (XDY) on influenza virus (IV)-induced F-actin restructuring and ERM phosphorylation regulated by the Rho/Rho kinase 1 (ROCK), p38 MAPK, and PKC signaling pathways in pulmonary microvascular endothelial cells (PMVECs). Methods: Serum containing XDY (XDY-CS; 13.8 g/kg) was acquired using standard protocols for serum pharmacology. Primary PMVECs were obtained from male Wistar rats and cultured. After adsorption of IV A (multiplicity of infection, 0.01) for 1 h, medium with 20% XDY-CS was added to the PMVECs. The distributions of F-actin and phosphorylated ERM were determined by confocal microscopy, and F-actin expression was measured by flow cytometry. The expression levels of ROCK1, phosphorylated myosin phosphatase target-subunit

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p38MAPK, Rho/ROCK and PKC pathways are involved in influenza-induced cytoskeletal rearrangement and hyperpermeability in PMVEC via phosphorylating ERM

Cited by 40 publications

References 42 publications

Strategies for the Development of Influenza Drugs: Basis for New Efficient Combination Therapies

Strategies for the Development of Influenza Drugs: Basis for New Efficient Combination Therapies

Ezrin and HNRNP expression correlate with increased virus release rate and early onset of virus‐induced apoptosis of MDCK suspension cells

Xijiao Dihuang Decoction combined with Yinqiao Powder reverses influenza virus-induced F-actin reorganization in PMVECs by inhibiting ERM phosphorylation

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